Impact of Ramadan fasting on glucose levels in women with gestational diabetes mellitus treated with diet alone or diet plus metformin: a continuous glucose monitoring study.

OBJECTIVE: Women with gestational diabetes mellitus (GDM) are categorized as at high risk for adverse events during Ramadan fasting. However, this is largely based on clinical opinion. In this study, we shed some light on what happens to glucose levels during Ramadan fasting. METHODS: This is a prospective observational study. A total of 32 patients with GDM were recruited; 10 patients, treated with diet only (group 1), to observe their glucose levels before fasting and 22 patients who insisted on fasting the month of Ramadan, 13 treated with diet only (group 2) and nine treated with diet plus metformin 500 mg twice daily (group 3), to evaluate their glucose levels during fasting. Interstitial glucose was monitored in all by using the iPro2 Professional continuous glucose monitoring (CGM) system. RESULTS: Mean glucose level was 116±21 mg/dL (6.16±1.16 mmol/L), 106±9 mg/dL (5.88±0.49 mmol/L) and 99±7 mg/dL (5.49±0.34 mmol/L) in groups 1, 2 and 3, respectively. Patients in group 1 had the lowest rate of hypoglycemia (50%), followed by patients in group 2 (60%), whereas patients in group 3 had the highest rate of hypoglycemia (78%). CONCLUSIONS: CGM data indicates that Ramadan fasting in women with GDM treated with diet alone or with diet plus metformin was associated with lower mean glucose levels and higher rates of hypoglycemia when compared with non-fasting glucose levels. Women with GDM should be advised against fasting during Ramadan until further data is available.

Leukocyte phenotype changes induced by specific immunotherapy in patients with birch allergy.

BACKGROUND: The underlying mechanisms of allergen-specific immunotherapy (SIT) are not fully understood. OBJECTIVES: The present study aimed to investigate how leukocyte phenotypes are affected by SIT. METHODS: Blood samples were taken from 10 patients with birch pollen--induced allergic rhinitis before, during, and immediately after SIT. Further samples were obtained after 1 year and 3 years. All samples were analyzed by flow cytometry and leukocyte differentiation. RESULTS: SIT caused a decrease in cell-bound immunoglobulin (Ig) E on granulocytes, along with a corresponding increase in the high-affinity IgG receptor. Accordingly, a lower level of allergen-specific IgE was found after 3 years. The treatment induced a decrease in neutrophil CD1 1b levels, a shift in monocyte subsets, and an increase in the number of activated T lymphocytes, manifested as an upregulation of CD69 and CD98, and an expansion of the CD4+CD25+ T-cell pool. CONCLUSION: The present study shows that the clinical effects of SIT are mirrored by systemic changes in cellular events and in antibodies, and offers new targets for immunomodulation.

Nasal CpG oligodeoxynucleotide administration induces a local inflammatory response in nonallergic individuals.

BACKGROUND: We have previously demonstrated the presence of toll-like receptor 9 in the nasal mucosa of both healthy and allergic individuals. CpG motifs, found in bacterial and viral DNA, elicit strong immunostimulatory effects via this receptor. CpG is known to skew the immune system towards a T helper 1 (Th1) profile, thereby suppressing Th2-driven allergic responses. This study was designed to examine the effects of CpG administration in the human nose. METHODS: Twenty subjects, of whom 10 suffered from seasonal allergic rhinitis (AR), were challenged intranasally with CpG outside pollen season. Symptom scores, nasal airway resistance (NAR), and nasal and pulmonary nitric oxide (NO) levels were assayed prior to challenge and 30 min, 6, 24 and 48 h post challenge. The presence of leukocytes and various cytokines were analyzed in nasal lavage (NAL) fluids before and after CpG exposure. RESULTS: Increased NAR, nasal NO production and secretion of interleukin (IL)-1beta, IL-6, and IL-8 were seen after CpG exposure. Further analysis revealed that this inflammatory response was more marked in healthy subjects than among patients with AR, although a higher basal inflammatory response was recorded in the allergic group. In vitro experiments suggest that the effects induced by CpG are mediated by epithelial cells and neutrophils. CONCLUSION: Nasal administration of CpG induces a local airway inflammation, more distinct among healthy than allergic individuals. The reduced responsiveness to CpG in allergic patients might be related to the ongoing minimal persistent inflammation. Results from cytokine analyses reflect the ability of CpG to induce a pro-inflammatory Th1-like immune response.

Lipopolysaccharide administration to the allergic nose contributes to lower airway inflammation.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory reaction not confined to a single local compartment, but rather involving the whole airway system. Allergens known to induce AR are not always the sole trigger of the inflammatory reaction as infections and organic dust might also cause exacerbations of rhinitis and associated conditions. OBJECTIVE: To examine the effects of intranasal lipopolysaccharide (LPS) exposure, as a surrogate for upper airway bacterial infections, in patients with symptomatic AR. METHODS: Fourteen patients with a history of moderate to severe pollen-induced AR were challenged intranasally with LPS. After 3-6 weeks, the same patients were challenged again, first with allergen and 24 h later with LPS. Nasal symptom scores, nasal lavage leucocyte counts and nasal airway resistance were assessed at 6-24 h after each provocation along with measurements of nitric oxide (NO) levels in the nose and lung. RESULTS: Six hours after the LPS challenge, an increased level of leucocytes could be obtained in the lavage fluid, but no symptoms were experienced and no increase in nasal resistance could be recorded. The NO production in the upper and lower airways was similar before and 6 h after the provocation. In contrast, in patients exposed to pollen before the LPS challenge, both the nasal and the pulmonary NO levels were enhanced. This was accompanied by an increase in leucocytes. CONCLUSION: The present study demonstrates a priming effect of allergen on the nasal response to LPS as well as the presence of a systemic link between airway mucosal sites in the upper and lower airways. This suggests that exogenously derived signals, like upper airway infections, can interfere with the initiation, maintenance and progression of asthma.

Efficacy of daily and monthly high-dose calciferol in vitamin D-deficient nulliparous and lactating women.

BACKGROUND: We previously found a high prevalence of vitamin D deficiency and low medication regimen compliance in Arab and East Indian women residing in the United Arab Emirates (UAE). The appropriate dosing regimen for improving vitamin D status in this population is not known. OBJECTIVE: We aimed to determine the efficacy of daily and monthly supplementation with vitamin D2, the only high-dose calciferol available in the UAE, in lactating and nulliparous women. DESIGN: Healthy lactating (n = 90) and nulliparous (n = 88) women were randomly assigned to consume 2000 IU vitamin D2/d or 60,000 IU vitamin D2/mo for 3 mo. Serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured by radioimmunoassay at baseline and every month. RESULTS: Most women had vitamin D deficiency [ie, 25(OH)D < 50 nmol/L] at study entry. Mean +/- SD 25(OH)D concentrations at 3 mo were significantly higher than baseline in both lactating (39.8 +/- 12.4 and 25.2 +/- 10.7 nmol/L, respectively) and nulliparous (40.4 +/- 23.4 and 19.3 +/- 12.2 nmol/L, respectively) women (P < 0.001 for both). In total, vitamin D supplementation was effective in achieving serum 25(OH)D concentrations of >or=50 nmol/L in 21 (30%) of 71 women at endpoint. CONCLUSIONS: Oral vitamin D2 supplementation with 2000 IU/d or 60,000 IU/mo for 3 mo was safe, and it increased serum 25(OH)D concentrations significantly; however, only a small proportion of the women studied achieved concentrations of >or=50 nmol/L. This suggests that, when sunlight exposure is limited, doses of vitamin D2 higher than those currently studied may be needed. Monthly dosing appears to be a safe and effective alternative to daily dosing.

Nerve growth factor enhances cholinergic innervation and contractile response to electric field stimulation in a murine in vitro model of chronic asthma.

BACKGROUND: Asthma is a chronic inflammatory disease characterized by airway hyper-responsiveness. Alterations in the neurogenic control are believed to contribute to the pathogenesis. Yet, the long-term interaction between nerves and inflammatory mediators, such as the neurotrophin nerve growth factor (NGF), are not fully understood much due to the absence of appropriate experimental assays. OBJECTIVE: To develop an ex vivo mouse organ culture assay and to investigate the effects of NGF on nerve-mediated airway contractions. METHOD: Mouse tracheal segments were cultured in periods of up to 16 days. Their contractile responses to electric field stimulation (EFS) were investigated. In addition, the effect of 4 days of NGF treatment was analysed using EFS and immunohistochemistry. RESULTS: EFS (0.2-25.6 Hz) induced reproducible and frequency-dependent cholinergic contractions of both fresh and cultured tracheal segments. The main part of the EFS response was blocked by tetrodotoxin or atropine. After 4 days in culture, regional differences appeared, with stronger EFS responses in distal than in proximal segments. More nerve fibres were seen in distal segments than in proximal segments. Treatment with NGF during 4 days of culture increased the innervation of the proximal segments, at the same time as the cholinergic contractile responses to EFS were enhanced dose-dependently. CONCLUSION: Culture of tracheal segments appears to be a suitable assay for the examination of long-term effects induced by inflammatory mediators on neurally mediated airway contractions. NGF treatment enhanced the cholinergic, nerve-dependent contractions and increased the amount of nerve fibres seen in the murine tracheal segments, suggesting a role for NGF in the development of airway hyper-responsiveness.

A computer vision based technique for 3-D sequence-independent structural comparison of proteins.

A detailed description of an efficient approach to comparison of protein structures is presented. Given the 3-D coordinate data of the structures to be compared, the system automatically identifies every region of structural similarity between the structures without prior knowledge of an initial alignment. The method uses the geometric hashing technique which was originally developed for model-based object recognition problems in the area of computer vision. It exploits a rotationally and translationally invariant representation of rigid objects, resulting in a highly efficient, fully automated tool. The method is independent of the amino acid sequence and, thus, insensitive to insertions, deletions and displacements of equivalent substructures between the molecules being compared. The method described here is general, identifies 'real' 3-D substructures and is not constrained by the order imposed by the primary chain of the amino acids. Typical structure comparison problems are examined and the results of the new method are compared with the published results from previous methods. These results, obtained without using the sequence order of the chains, confirm published structural analogies that use sequence-dependent techniques. Our results also extend previous analogies by detecting geometrically equivalent out-of-sequential-order structural elements which cannot be obtained by current techniques.

An efficient automated computer vision based technique for detection of three dimensional structural motifs in proteins.

As the number of available three dimensional coordinates of proteins increases, it is now recognized that proteins from different families and topologies are constructed from independent motifs. Detection of specific structural motifs within proteins aids in understanding their role and the mechanism of their operation. To aid in identification and use of these motifs it has become necessary to develop efficient methods for systematic scanning of structural databases. To date, methods of structural protein comparison suffer from at least one of the following limitations: (1) are not fully automated (require human intervention), (2) are limited to relatively similar structures, (3) are constrained to linear alignments of the structures, (4) are sensitive to insertions, deletions or gaps in the sequences or (5) are very time consuming. We present a method to overcome the above limitations. The method discovers and ranks every piece of structural similarity between the structures compared, thus allowing the simultaneous detection of real 3-D motifs in different domains, between domains, in active sites, surfaces etc. The method uses the Geometric Hashing Paradigm which is an efficient technique originally developed for Computer Vision. The algorithm exploits the geometrical constraints of rigid objects, it is especially geared towards recognition of partial structures in rigid objects belonging to large data bases and is straightforwardly parallelizable. Computer Vision techniques are for the first time applied to molecular structure comparison, resulting in an efficient, fully automated tool. The method has been tested in a number of cases, including comparisons of the haemoglobins, immunoglobulins, serine proteinases, calcium binding proteins, DNA binding proteins and others. In all examples our results were equivalent to the published results from previous methods and in some cases additional structural information was obtained by our method.

Alzheimer's disease antibodies bind specifically to a neurofilament protein in Torpedo cholinergic neurons.

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and neuritic plaques and by the degeneration of central cholinergic neurons. Recent studies indicated the presence of antibodies in the sera and cerebrospinal fluid of AD patients which react with neuronal tissue and which recognize cholinergic neurons. In order to identify the cholinergic antigens against which the AD antibodies are directed, we have recently used the purely cholinergic electromotor neurons of the electric fish Torpedo which are chemically homogenous and cross-react antigenically with mammalian cholinergic neurons. This study revealed that immunoglobulins (IgG) from sera of AD patients bind specifically to an antigen in Torpedo electromotor neurons with an apparent molecular weight of 200 kDa. In the present report we attempt to characterize this antigen. The similarity in size of this protein to that of the heavy neurofilament subunit (NF-H) and the association of neurofilaments with plaques and tangles prompted us to examine the possibility that it is a neurofilament protein. Our findings show that IgG from sera of AD patients bind to the NF-H protein of Torpedo cholinergic neurons. Comparison of the binding of AD and control IgG to Torpedo cholinergic NF-H revealed that AD IgG bind to this neurofilament protein more readily than do control IgG. In contrast, AD and control IgG bind similarly to NF-H obtained from the chemically heterogenous Torpedo spinal cord and rat brain. These findings suggest that AD sera contain a repertoire of anti-NF-H IgG and that a subpopulation of these antibodies whose levels are significantly elevated in AD binds to epitopes highly enriched in Torpedo cholinergic NF-H.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum antibodies to cholinergic neurons in Alzheimer's disease.

Alzheimer's disease (AD) is associated with degenerative changes in nuclei of the basal forebrain which provide most of the cholinergic innervation of the cortex and hippocampus. Although the etiology and pathogenesis of AD are not known, several reports indicate the involvement of immunological mechanisms. In the present work we examined the existence of antibodies in sera of AD patients which bind specifically to cholinergic neurons. As antigen we employed the purely cholinergic electromotor neurons of the electric fish Torpedo which are chemically homogeneous and cross react antigenically with human and other mammalian cholinergic neurons. Our findings show that immunoglobulins (IgG) from sera of AD patients bind to the heavy neurofilament subunit (NF-H) of these neurons. Comparison of the binding of AD and control IgG to Torpedo cholinergic NF-H revealed that AD IgG bind to this neurofilament protein more than control IgG. In contrast, AD and control IgG bind similarly to NF-H obtained from the chemically heterogeneous Torpedo spinal cord and from rat brain. These findings suggest that AD sera contain a repertoire of anti NF-H IgG and that a subpopulation of these antibodies, whose levels are significantly elevated in AD, binds to epitopes highly enriched in Torpedo cholinergic NF-H. The diagnostic potential of these AD antibodies is discussed.

Antibodies to cholinergic neurons in Alzheimer's disease.

Alzheimer's disease (AD) is associated with degenerative changes in nuclei of the basal forebrain which provide most of the cholinergic input to the cortex and hippocampus and with a reduction in presynaptic cholinergic parameters in these areas. Although the etiology and pathogenesis of AD are not known, several reports indicate the involvement of immunological mechanisms. In the present work we examined the existence of antibodies in sera of AD patients that bind specifically to cholinergic neurons. As antigens we employed the purely cholinergic electromotor neurons of the electric fish Torpedo which are chemically homogeneous and cross-react antigenically with human and other mammalian cholinergic neurons. Our findings show that immunoglobulins from sera of AD patients bind to a specific antigen (molecular mass 200 kilodaltons) in the cell bodies and axons of Torpedo electromotor neurons and that the levels of such antibodies are significantly higher in AD patients than in controls. The possible role of these antibodies in the cholinergic dysfunction in AD and their diagnostic potential are discussed.